The invention relates to novel compounds which are used in the pharmaceutical industry for the production of medicaments.
International Patent Applications WO91/12251 and WO93/07146 describe phthalazinones having bronchodilating and antiasthmatic properties. International Patent Application WO94/12461 describes 3-aryl-pyridazin-6-one derivatives as selective PDE4 inhibitors. European Patent Application EP 0722936 describes fused pyridazine compounds with cGMP-PDE inhibiting activity. In J. Med. Chem. 1993, 4052-4060 Yamaguchi et al. describe phthalazinones having thromboxane A2 synthetase inhibitory and bronchodilatory activities.
It has been found that the phthalazinones described in greater detail below, which differ from the previously published compounds by a different substitution pattern have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I 
in which
R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-4C-alkyl and
R3 is hydrogen or 1-4C-alkyl,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,
Het represents a heterocycle having the meaning 
wherein
R4 is R5, xe2x80x94CmH2mxe2x80x94R6 or xe2x80x94CpH2pxe2x80x94Yxe2x80x94Ar
R5 is hydrogen, 1-8C-alkyl, 3-10C-cycloalkyl, 3-7C-cycloalkylmethyl, 7-10C-polycycloalkyl an unsubstituted phenyl or pyridyl radical or a phenyl radical substituted by R51 and/or R52, in which
R51 is 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, cyano, nitro, halogen, hydroxyl, amino, mono- or di-1-4C-alkylamino, imidazolyl or tetrazolyl, and
R52 is 1-4C-alkyl, 1-4C-alkoxy, nitro or halogen,
R6 is hydroxyl, halogen, nitro, cyano, carboxyl, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkyl-amino, aminocarbonyl or mono- or di-1-4C-alkylaminocarbonyl,
Y is O (oxygen), S (sulphur) or a covalent bond,
Ar is an unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl, quinolyl, purinyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, coumarinyl, imidazolyl, pyrazolyl, oxazolyl or pyrrolyl radical or a phenyl radical substituted by R7 and/or R8, in which
R7 is hydroxyl, halogen, nitro, cyano, 1-4C-alkyl, 1-4C-alkoxy, carboxyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino, imidazolyl or tetrazolyl,
R8 is halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy,
m is an integer from 1 to 4,
p is an integer from 1 to 4,
and the salts of these compounds.
1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.
1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred.
As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionally interrupted by an oxygen or sulphur atom, may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydropyran and the tetrahydrothiophen ring.
According to the invention, the group Het is represented by a heterocycle having the meaning a, b or c, of which the heterocycles having the meaning a or b are preferred.
Possible groups xe2x80x94CpH2pxe2x80x94, xe2x80x94CmH2mxe2x80x94 are straight chain or branched groups. Examples which may be mentioned are the butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene and the methylene group.
1-8C-Alkyl is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples are the octyl, isooctyl (6-methylheptyl), heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
3-10C-Cycloalkyl stands, for example, for cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
3-7C-Cycloalkylmethyl stands for a methyl radical, which is substituted by one of the above-mentioned 3-7C-cycloalkyl radicals.
7-10C-polycycloalkyl stands for 7-10C-bicycloalkyl or 7-10C-tricycloalkyl groups, such as for example, bornyl, norbornyl or adamantyl.
Halogen within the meaning of the present invention is bromine, chlorine and fluorine.
1-4C-Alkoxycarbonyl is a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is bonded. Examples are the methoxycarbonyl [CH3Oxe2x80x94C(O)xe2x80x94] and the ethoxycarbonyl [CH3CH2Oxe2x80x94C(O)xe2x80x94] radical.
Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, one or two of the above-mentioned 1-4C-alkyl radicals. Preferred are the di-1-4C-alkylamino radicals, especially the dimethylamino, the diethylamino and the diisopropylamino radical.
Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the above-mentioned mono- or di-1-4C-alkylamino radicals. Examples which may be mentioned are the N-methyl- the N,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and the N-isopropylamino-carbonyl radical.
An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino [C3H7C(O)NHxe2x80x94] and the acetylamino radical [CH3C(O)NHxe2x80x94].
Carboxy-1-4C-alkyl radical are, for example, the carboxymethyl (xe2x80x94CH2COOH) and the carboxyethyl (xe2x80x94CH2CH2COOH) radicals.
Suitable salts for compounds of the formula Ixe2x80x94depending on substitutionxe2x80x94are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts with the inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparationxe2x80x94depending on whether a mono- or polybasic acid is concerned and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
On the other hand, salts with bases arexe2x80x94depending on substitutionxe2x80x94also suitable. As examples of salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, megiumine or guanidinium salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts, which can be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
According to expert""s knowledge the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I as well as all solvates and in particular all hydrates of the salts of the compounds of formula I.
Compounds of the formula I to be emphasized are those, in which
R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-4C-alkyl and
R3 is hydrogen or 1-4C-alkyl,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,
Het represents a heterocycle having the meaning 
wherein
R4 is R5, xe2x80x94CmH2mxe2x80x94R6 or xe2x80x94CpH2pxe2x80x94Yxe2x80x94Ar,
R5 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, bomyl, norbomyl, adamantyl or an unsubstituted or by R51 substituted phenyl radical, in which
R51 is 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl or halogen,
R6 is hydroxyl, halogen, carboxyl or 1-4C-alkoxycarbonyl,
Y is O (oxygen) or a covalent bond,
Ar is an unsubstituted phenyt, pyridyl, purinyl, benzimidazolyl, benzotriazolyl, imidazolyl, pyrazolyl, or pyrrolyl radical, or a phenyl radical substituted by R7, in which
R7 is halogen, nitro, cyano, 1-4C-alkyl, 1-4C-alkoxy, carboxyl, carboxy-1-2C-alkyl, 1-4C-alkoxy-carbonyl or tetrazolyl,
m is an integer from 1 to 4,
p is an integer from 1 to 4,
and the salts of these compounds.
Compounds of the formula I which are particularly to be emphasized are those, in which
R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-4C-alkyl and
R3 is hydrogen or 1-4C-alkyl,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked cyclopentane or cyclohexane ring,
Het represents a heterocycle having the meaning 
wherein
R4 is R5, xe2x80x94CmH2mxe2x80x94R6 or xe2x80x94CpH2pxe2x80x94Yxe2x80x94Ar,
R5 is hydrogen, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, adamantyl or an unsubstituted or by R51 substituted phenyl radical, in which
R51 is carboxyl or 1-4C-alkoxycarbonyl,
R6 is hydroxyl or halogen,
Y is O (oxygen) or a covalent bond,
Ar is an unsubstituted phenyl, pyridyl, imidazolyl or purinyl radical, or a phenyl radical substituted by R7, in which
R7 is cyano, 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl or tetrazolyl,
m is an integer from 1 to 4,
p is an integer from 1 to 4,
and the salts of these compounds.
One embodiment of the compounds of the formula I particularly to be emphasized are those, in which
R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1C-alkyl and
R3 is hydrogen or 1-4C-alkyl,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked cyclopentane or cyclohexane ring,
Het represents a heterocycle having the meaning 
wherein
R4 is R5, xe2x80x94CmH2mxe2x80x94R6 or xe2x80x94CpH2pxe2x80x94Yxe2x80x94Ar,
R5 is hydrogen, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, adamantyl or phenyl,
R6 is hydroxyl or halogen,
Y is O (oxygen) or a covalent bond,
Ar is an unsubstituted phenyl or pyridyl radical, or a phenyl radical substituted by R7, in which
R7 is cyano, 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl or tetrazolyl,
m is an integer from 1 to 4,
p is an integer from 1 to 4,
and the salts of these compounds.
Preferred compounds of the formula I are those, in which
R1 is methoxy or difluoromethoxy,
R2 is methyl,
R3 is hydrogen,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked cyclopentane ring,
Het represents a heterocycle having the meaning 
wherein
R4 is R5, xe2x80x94CmH2mxe2x80x94R6 or xe2x80x94CpH2pxe2x80x94Yxe2x80x94Ar,
R5 is hydrogen, 3-7C-cycloalkyl or an unsubstituted or by R51 substituted phenyl radical, in which
R51 is carboxyl,
R6 is hydroxyl or halogen,
Y is O (oxygen) or a covalent bond,
Ar is an unsubstituted phenyl, pyridyl, imidazolyl or purinyl radical, or a phenyl radical substituted by R7, in which
R7 is cyano, carboxyl or tetrazolyl,
m is an integer from 1 to 4,
p is an integer from 1 to 4,
and the salts of these compounds.
One embodiment of the preferred compounds of the formula I are those compounds in which
R1 is methoxy or difluoromethoxy,
R2 is methyl,
R3 is hydrogen,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked cyclopentane ring,
Het represents a heterocycle having the, meaning 
wherein
R4 is R5, xe2x80x94CmH2mxe2x80x94R6 or xe2x80x94CpH2pxe2x80x94Yxe2x80x94Ar,
R5 is hydrogen, 3-7C-cycloalkyl or phenyl,
R6 is hydroxyl or halogen,
Y is O (oxygen) or a covalent bond,
Ar is an unsubstituted phenyl, pyridyl, imidazolyl or purinyl radical, or a phenyl radical substituted by R7, in which
R7 is cyano, carboxyl or tetrazolyl,
m is an integer from 1 to 4,
p is an integer from 1 to 4,
and the salts of these compounds.
Especially preferred compounds of formula I are those, in which
R1 is methoxy,
R2 is methyl,
R3 is hydrogen,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked cyclopentane ring,
Het represents a heterocycle having the meaning 
wherein
R4 is R5, xe2x80x94CmH2mxe2x80x94R6 or xe2x80x94CpH2pxe2x80x94Yxe2x80x94Ar,
R5 is hydrogen, cyclopentyl, cycloheptyl, phenyl or p-carboxyphenyl,
R6 is hydroxyl,
Y is O (oxygen) or a covalent bond,
Ar is an unsubstituted phenyl, pyridyl, imidazolyl or purinyl radical, or a phenyl radical substituted by R7, in which
R7 is cyano, carboxyl or tetrazoyl,
m is an integer from 1 to 4,
p is an integer from 1 to 4,
and the salts of these compounds.
One embodiment of the especially preferred compounds of formula I are those compounds in which
R1 is methoxy,
R2 is methyl,
R3 is hydrogen,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked cyclopentane ring,
Het represents a heterocycle having the meaning 
wherein
R4 is R5, xe2x80x94CmH2mxe2x80x94R6 or xe2x80x94CpH2pxe2x80x94Yxe2x80x94Ar,
R5 is hydrogen, cyclopentyl, cycloheptyl or phenyl,
R6 is hydroxyl,
Y is O (oxygen) or a covalent bond,
Ar is an unsubstituted phenyl, pyridyl, imidazolyl or purinyl radical, or a phenyl radical substituted by R7, in which
R7 is cyano, carboxyl or tetrazoyl,
m is an integer from 1 to 4,
p is an integer from 1 to 4,
and the salts of these compounds.
Exemplary compounds according to the invention are listed in the following tables:
The compounds of formula I are chiral compounds with a chiral center in the dihydrofuran-ring, if the substituents xe2x80x94R2 and xe2x80x94CH2R3 are not identical. However, preferred are those compounds, in which the substituents xe2x80x94R2 and xe2x80x94CH2R3 are identical or together and with inclusion of the carbon atom to which they are bonded form a spiro-connected 5-, 6- or 7-membered hydrocarbon ring. Additional chiral centers exist in the positions 4a and 8a in those cases, in which Het represents a heterocycle having the meaning (a) or (b): 
Therefore the invention includes all conceivable pure diastereomers and pure enantiomers, as well as all mixtures thereof independent from the ratio, including the racemates. Preferred are those compounds, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated. Especially preferred are in this connection those compounds, in which the absolute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a. Racemates can be split up into the corresponding enantiomers by methods known by the person skilled in the art. Preferably the racemic mixtures are seperated into two diastereomers with the help of an optical active separation agent on the stage of the cyclohexanecarboxylic acids (for example, starting compound B) or the 1,2,3,6-tetrahydrobenzoic acids (for example, starting compounds A and D). As separation agents may be mentioned, for example, optical active amines such as the (+)- and (xe2x88x92)-forms of aphenylethylamine and ephedrine, or the optical active alkaloids cinchonine, cinchonidine and brucine.
The invention further relates to a process (see scheme 1) for the preparation of compounds of formula I and their salts. 
The Process Comprises
a) reacting keto acids of formula IIa (IIb, IIc) or one of their reactive derivatives, in which R1, R2 and R3 have the above-mentioned meanings in a first step with hydrazine hydrate to compounds of formula Ia (Ib, Ic), in which R1, R2 and R3 have the above-mentioned meanings and R4 stands for hydrogen (H).
If desired, these compounds can be reacted with alkylating agents of formula R4-X, in which R4 has the above-mentioned meanings [exception: R4 does not represent hydrogen (H)] and X represents a leaving group to give further compounds of formula I, in which R1, R2, R3 and R4 have the above-mentioned meanings [exception: R4 does not represent hydrogen (H)].
b) reacting, alternatively to procedure a), keto acids of formula IIa (IIb, IIc) or one of their reactive derivatives, in which R1, R2 and R3 have the above-mentioned meanings with suitable hydrazine derivates of formula R4-NH-NH2, in which R4 has the above-mentioned meanings [exception: R4 does not represent hydrogen (H)], to give compounds of the formula Ia (Ib, Ic), in which R1, R2, R3 and R4 have the above-mentioned meanings [exception: R4 does not represent hydrogen (H)].
The conversion of the keto acids of formula IIa (IIb, IIc) or one of their reactive derivatives with hydrazine hydrate [according to procedure a)] respectively with suitable hydrazine-derivates of the formula R4-NH-NH2 [according to procedure b)] is advantageously carried out with one to five equivalents of hydrazine hydrate respectively the suitable hydrazine derivates of formula R4-NH-NH2, which simultaneously can be used as solvent. More suitable is, however, to use an additional appropriate solvent. As inert solvents are preferably used alcohols such as methanol, ethanol, isopropanol, n-butanol, isoamylalcohol, glycols and their ethers such as ethylene glycol, diethylene glycol, ethylene glycol monomethyl or monoethyl ether, carboxylic acids such as formic acid, acetic or propionic acid, suitable mixtures of the above-mentioned solvents, as well as mixtures with water, for example aqueous ethanol, further ethers, especially water soluble ethers such as tetrahydrofuran, dioxane or ethylene glycol dimethylether; further toluene or benzene, especially when the method of azeotropic destilation is used to remove the reaction water.
The reaction temperatures are suitably between 0 and 200xc2x0 C., preferably between 20 and 100xc2x0 C.; the reaction times are preferably between 1 and 48 hours.
Suitable reactive derivatives of the keto acids of formula IIa (IIb, IIc) which may be mentioned in this context are, for example, esters, especially methyl and ethyl esters, nitrils and acid halides, such as acid chlorides or acid bromides. They can be prepared, for example, starting from the corresponding keto acids of formula IIa (IIb, IIc), by methods which are known by the person skilled in the art.
The conversion of compounds of formula Ia (Ib, Ic), in which R1, R2 and R3 have the above-mentioned meanings and R4 represents hydrogen (H) with alkylating agents of the formula R4-X, in which R4 has the above-mentioned meanings [with the exception of hydrogen(H)] and X represents a suitable leaving group, is carried out in a manner, which is known by a person skilled in the art.
In a first step, the hydrogen atom (H) of the NH-group of the compounds of formula Ia (Ib, Ic), in which R4 represents a hydrogen atom (H) is removed by a base such as, for example, potassium carbonate, sodium hydroxide, sodium hydride, sodium methanolate, sodium ethanolate or buthyllithium in a suitable inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or diethylether. The bases are preferably used in more than an equimolar ratio.
The alkylation is then carried out by adding an appropriate alkylating agent of the formula R4-X.
Examples of suitable leaving groups X which may be mentioned are halogen atoms, especially chlorine, or hydroxyl groups activated by esterification (for example with p-toluenesulfonic acid).
Suitable alkylating agents of the formula R4-X are for example iodomethane, bromoethane, 1-bromo-propane, 2-bromopropane, 3-bromopentane, cyclopentylbromide, bromomethylcyclohexane, cycloheptylbromide, 4-chloromethylbenzoic acid, 3-bromomethylbenzoic acid, 4-chloromethylphenylacetic acid, 2-methoxybenzy chloride, 3-methoxybenzylchloride, 4-methoxybenzylchloride, 3,5-dimethoxybenzyl-chloride, 2-chlorobenzylchloride, 2-picolylchloride, 3-picolylchloride, 4-picolylchloride and 2-bromoethyl-benzene.
Examples for suitable hydrazine-derivates of formula R4-NH-NH2 are methylhydrazine, 2-hydroxyethyl-hydrazine, phenylhydrazine, benzylhydrazine, 4-tert-butylhydrazine, 2-bromophenylhydrazine, 4-chloro-phenylhydrazine, 4-fluorophenylhydrazine, 2,4-dichlorophenylhydrazine, 4-chloro-o-tolylhydrazine, 2,5-dimethylphenylhydrazine, 2,4-dinitrophenylhydrazine, 4-methoxyphenylhydrazine, 3-nitrophenyl-hydrazine, p-tolylhydrazine and 4-hydrazinobenzoic acid.
Keto acids of the formula IIa (IIb, IIc), in which R1, R2 and R3 have the above-mentioned meanings can, for example, be prepared from compounds of the formula III, in which R1, R2 and R3 have the above-mentioned meanings and Z represents hydrogen (H) by Friedel-Crafts acylation with hexahydrophthalic anhydride, 1,2,3,6-tetrahydro-phthalic anhydride or phthalic anhydride. The Friedel-Crafts acylation is carried out in a manner which in known by the skilled person (for example as described in M. Yamaguchi et al., J. Med. Chem. 36: 4052-4060, 1993) in presence of a suitable catalyst, such as for example, AlCl3, ZnCl2, FeCl3 or iodine, in an appropriate inert solvent, such as methylene chloride or nitrobenzene or another inert solvent such as diethyl ether, preferably at raised temperature, especially at the boiling point of the solvent being used.
Alternatively, the compounds of formula IIa (IIb, IIc), in which R1, R2 and R3 have the above-mentioned meanings, can be prepared from compounds of the formula III, in which RI R2 and R3 have the above-mentioned meanings and Z represents a halogen atom through reaction with hexahydrophthalic anhydride, 1,2,3,6-tetrahydro-phthalic anhydride, or phthalic anhydride.
The reaction is carried out in a manner which is known by a person skilled in the art, for example
a) by activating compounds of formula III, in which R1, R2, R3 and Z have the above-mentioned meanings, by a lithium/halogen exchange reaction at low temperatures (preferably at xe2x88x9260 to xe2x88x92100xc2x0 C.) in an appropriate inert solvent such as tetrahydrofuran or diethylether, preferably under an atmosphere of inert gas, followed by reaction of the lithiated compounds the above-mentioned anhydrides, or
b) by converting compounds of formula III, in which R1, R2, R3 and Z have the above-mentioned meanings, in a suitable inert solvent such as, for example, tetrahydrofuran or diethyl ether into the corresponding Grignard compounds of formula III, in which Z represents MgCl, MgBr or Mgl followed by reaction of the Grignard compounds with the above-mentioned anhydrides.
Compounds of formula III, in which R1, R2 and R3 have the above-mentioned meanings and Z represents a hydrogen (H) or halogen atom, are known or can be prepared according to the reaction scheme 2. 
By way of example, the preparation of compounds of the formula III is described in the following examples under xe2x80x9cstarting compoundsxe2x80x9d. The preparation of further compounds of formula III can be carried out in an analogous manner.
Additionally, it is possible to convert one functional group of a compound of formula I (Ia, Ib, Ic) to another functional group by customary methods and reactions.
Thus, if desired, compounds of formula I with suitable functional groups can be converted into further compounds of formula I.
For instance, compounds of formula I, in which R4 comprises an ester can be converted by acidic or alkaline saponification to the corresponding carboxylic acid.
Suitably, the conversions are carried out analogous to methods which are familiar per se to the person skilled in the art, for example, in the manner which is described in the following examples.
The substances according to the invention are isolated and purified in a manner known per se, e.g. by destining off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn, can be converted into salts. In this manner, pharmacologically non-tolerable salts can be converted into pharmacologically tolerable salts.